Defining novel drivers and predictive signatures of metastasis in osteosarcoma th

项目摘要/摘要 绝大多数癌症引起的死亡(90%)不是由原发肿瘤引起的，而是由扩散引起的 癌细胞从发源地转移到身体的其他部位--这一过程称为转移。尽管 据了解，大多数癌症治疗都是针对原发肿瘤，而不是转移性病变。一个 开发靶向抗转移疗法的主要限制是缺乏对生物学的了解 癌细胞中这一过程的驱动因素。最近的一些研究已经证明，表观遗传学 识别整个细胞基因组中的基因增强子元件的标记可以高度预测特定细胞类型 基因表达模式，因此对细胞行为有很高的信息量。一项这样的研究应用于 表观遗传学增强子谱对癌症的研究揭示了对分子的前所未有的洞察 导致肿瘤形成的变化。在拟议的研究中，这种方法将被应用于调查 表观遗传学改变推动了最常见的原发骨肿瘤的转移过程， 骨肉瘤。这是一种高度侵袭性的实体肿瘤，通常影响青少年，通常导致 死于肺转移的进展。不幸的是，这些患者的长期结果并非如此。 经过30多年的改进。通过应用这种表观遗传学方法，这个项目试图获得洞察力 研究骨肉瘤转移的分子基础，目的是确定“转移驱动因素” 这可能作为合适的治疗靶点以及预测肿瘤转移风险的分子标记 骨肉瘤患者。成功完成这些研究不仅提供了改进的潜力 骨肉瘤患者的预后，但也获得了对转移过程的洞察，总的来说， 可能会为其他类型癌症的研究提供参考。

PROJECT SUMMARY/ABSTRACT The large majority of cancer-caused deaths (>90%) do not result from the primary tumor, but from the spread of cancer cells from their location of origin to other sites of the body - a process known as metastasis. Despite this understanding, most cancer treatments are designed to target the primary tumor, not metastatic lesions. A major limitation in developing targeted anti-metastatic therapies is a lack of understanding of the biological drivers of this process in cancer cells. It has been demonstrated by a number of recent studies that epigenetic marks identifying gene enhancer elements across a cell's genome are highly predictive of cell-type-specific patterns of gene expression and are therefore highly informative of cellular behavior. One such study applying epigenetic enhancer profiling to the study of cancer has revealed unprecedented insight into the molecular alterations that drive tumor formation. In the proposed studies, this approach will be applied to investigate epigenetic alterations driving the process of metastasis in the most common primary tumor of bone, osteosarcoma. This is a highly aggressive solid tumor that commonly affects adolescents, often resulting in death from metastatic progression to the lung. Unfortunately, long-term outcomes for these patients have not improved for over 30 years. Through application of this epigenetic approach, this project seeks to gain insight into the molecular underpinnings of osteosarcoma metastasis with the goal of identifying "metastatic drivers" that may serve as suitable therapeutic targets as well as molecular signatures predictive of metastatic risk in osteosarcoma patients. Successful completion of these studies not only offer the potential to improve outcomes for osteosarcoma patients, but also to gain insight into the process of metastasis, in general, that may inform the study of other types of cancer.